This is a comprehensive study of the mechanisms of differentiation and development and the action of thyroid hormone using amphibian metamorphosis as a model system. Particular attention is paid to the initiating mechanisms by which thyroid hormones trigger the metamorphic process. This includes a study of thyroid hormones receptors and effects on genetic expression originating in the cell nuclei. We also hope to contribute to knowledge of comparative biochemistry, endocrinology, embryonic development and biochemical evolution. Emphasis will be placed on three objectives: (1) Characterization of the nuclear receptors of the thyroid hormone in anurans will be continued. This includes the study of the effect of temperature, subcellular distribution and cytoplasmic binding of T3 and T4, the binding of T3 to tadpole chromatin, and the isolation and properties of nuclear-T3 binding proteins. Relationships to the onset and completion of metamorphosis, specific tissue response, and finally, to hormonal states in other amphibian systems will be sought. (2) We will examine the effects of thyroid hormone on the nucleus and on macromolecular biosynthesis during spontaneous and induced metamorphosis. This includes an analysis of changes in mRNA biosynthesis and processing, possible effects on mitochondrial DNA, RNA and protein and changes in the rate of protein synthesis and degradation. (3) Finally, these ideas and results will be analyzed for the basis of endocrine control of development blocks in other amphibia. The urodeles provide a rich reservoir of biological systems, frequently incomplete or modified in their endocrine mechanisms and developmental expressions. Thus we hope to answer basic questions on the endocrine mechanisms which have evolved to reach the present state of vertebrate development.